The invention features methods for identifying compounds that modulate the activity of Type 2 phosphatidylinositol 5-phosphate 4-kinase (PI5P4K; e.g., PI5P4Kα or PI5P4Kβ). Inhibitors of PI5P4K can be used in, for example, the treatment or prevention of cell proliferation disorders (e.g., the prevention of tumor cell growth in p53 mutated cancers).
Phosphatidylinositol (PI) signaling has been shown to impact a large and diverse number of cellular processes including proliferation, survival, and cytoskeletal organization. One particular species of PI, phosphatidylinositol 5-phosphate (PI5P), has been implicated in the regulation of the tumor suppressor ING2 and the oncogene AKT. The phosphatidylinositol 5-phosphate 4-kinase (PI5P4K) family (α, β, γ isoforms) catalyzes the conversion of PI5P to PI4, 5 P2. These enzymes therefore represent one means by which cells can regulate endogenous PI5P levels. Mice deficient for PI5P4Kβ (PI5P4Kβ−/−) have been shown to exhibit enhanced insulin sensitivity and activation of AKT in skeletal muscle.
As described herein, studies using PI5P4Kα−/− mice and double mutant PI5P4kα−/−β−/− mice indicate that complete loss of PI5P4Kα/β activity results in perinatal lethality while partial loss of PI5P4Kα/β activity leads to dramatic growth retardation. Both α and β isoforms of PI5P4K have been shown to be highly expressed in cancer cells, particularly in breast cancer cells. Based on a combination of cellular and microarray expression analyses, PI5P4K is now shown to be required for the proliferation of breast cancer cells. Further, PI5P4K deficiency restricts tumorigenesis in vivo.
The data demonstrate a critical role for PI5P4K in tumor cell growth and support a potential role in oncogenesis for PI5P4K. By inhibiting PI5P4K, a useful strategy can be developed for the prevention of tumor cell growth in p53-mutated cancers. TP53 gene is a key tumor suppressor gene and the most frequently mutated gene in human cancers. Its deletion or mutation has been found in more than 50% of human cancers, and currently more than ten million people have tumors with p53 inactive mutations. However, it has been difficult to develop drugs for targeting p53. Inhibitors for PI5P4K can be useful drugs to induce synthetic lethality of p53-mutated tumors.
Accordingly, methods for the identification of compounds that modulate PI5P4K would be useful. Further, PI5P4K inhibitor compounds that are identified according to these methods can be useful in the treatment and prevention of cancer, as well as being useful as a tool to further investigate PI5P4K function.